Pharmaceutical co-crystallization has attracted great amount of academic, industrial and therapeutic interests by co-crystallization of two or more pure compounds with crystal engineering to create a new functional material. Specifically, pharmaceutical co-crystals are defined as “co-crystals in which the target molecule or ion is an active pharmaceutical ingredient, API, and it bonds to the co-crystal former(s) through hydrogen bonds.” Almarsson M. and Zaworotko J., Chem. Commun., 2004: 1889. Pharmaceutical co-crystals are nonionic supramolecular complexes and can be used to improve physiochemical properties such as solubility, stability and bioavailability in pharmaceutical development without changing the chemical composition of the active pharmaceutical ingredient (API).
Carboplatin, one of the second-generation antitumor drugs of platin analogues, has received worldwide approval and use due to its lower toxicity in comparison to cisplatin. Unfortunately, although to a milder degree compared to first generation platins, carboplatin still results in a number of side effects, such as myelosuppression. In addition, carboplatin may be used only for a limited spectrum of cancers. Therefore, the search continues for orally active carboplatin analog compounds that are less toxic, cause less drug-resistance and provide more versatility.
Consequently, it is desirable to improve the physiochemical and therapeutic properties of cisplatin, carboplatin and other platin with co-crystallization technology. In some cases, there is no need to change the basic structure of the platin as the API, while properties such as solubility, stability, permeability and bioavailability can be improved. For example, it would be possible to significantly enhance the bioavailabiltiy of a platin API with co-crystallization, so that the co-crystal can be therapeutically effective in certain environment of use and maintain the level for a prolonged period of time.
The present invention provides a series of co-crystals of carboplatin, where one of the co-crystal formers is a cyclic amide. The co-crystals of this invention may satisfy one or more of the targeted objectives, such as but not limited to increased solubility, stability and bioavailability and more versatility in pharmaceutical use.